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IL-10/TGF-β-Treated Dendritic Cells, Pulsed with Insulin, Specifically Reduce the Response to Insulin of CD4+ Effector/Memory T Cells from Type 1 Diabetic Individuals

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Abstract

Introduction

Diabetogenic autoreactive T cells with effector/memory characteristics are described in type 1 diabetes patients (T1D). Alternatively activated dendritic cells (aaDCs) have been regarded as promising tools for clinical application in autoimmune diseases (ADs), although their ability to induce antigen-specific tolerance in T cells derived from ADs has yet to be determined.

Methods

Monocyte-derived dendritic cells (DCs) were produced utilizing GM-CSF and IL-4, and aaDCs by adding IL-10 and TGF-β (10/TGF-DC) during differentiation. Both cell groups were insulin-loaded, maturated with lipopolysaccharide, and cocultured with autologous effector/memory T cells derived from T1D individuals, in order to evaluate the induction of insulin-specific tolerance.

Results and Discussion

In five of eight T1D patients analyzed in vitro, 10/TGF-DC were able to induce insulin-specific tolerance in effector/memory CD4+ T cells (50.4% ± 13.2 less proliferation), without affecting the proliferative response to an unrelated antigen (candidin). Tolerance induction was dependent on the current activation state of CD4+ T cells in each patient. 10/TGF-DC-stimulated T cells acquired an IL-2lowIFN-γlowIL-10high cytokine profile, and their hyporesponsiveness could be reverted upon exposure to IL-2. This study shows a perspective about the in vitro ability of monocyte-derived 10/TGF-DC to induce antigen-specific tolerance in effector/memory T cells generated during the course of an autoimmune disease.

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Abbreviations

ADs:

autoimmune diseases

cTC:

control T lymphocytes

iDCs:

immature DC

LPS:

lipopolysaccharide

mDCs:

mature DC

MFI:

mean fluorescence intensity

rTC:

T cells with no prior stimulation in vitro

T1D:

type 1 diabetes

tDCs:

tolerogenic DC

10/TGF-DC:

DC generated with IL-10/TGF-β1

tTC:

tolerant T lymphocytes

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Acknowledgements

The authors would like to thank to Prof. Eitan Israeli, Dr. Gisele Goddard, and Jana Petrikova, M.D., for valuable discussions and technical assistance. HTA has a postdoctoral fellowship of ICyTDF (BI09-532). This work was supported in part by Federico Foundation.

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Authors and Affiliations

  1. Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, 52662, Israel

    Honorio Torres-Aguilar, Miri Blank & Yehuda Shoenfeld

  2. Department of Molecular Biomedicine, Centro de investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico

    Carmen Sánchez-Torres

  3. Direction of Education and Research, Hospital de Especialidades Centro Médico La Raza, IMSS, Mexico City, Mexico

    Luis J. Jara

  4. Universidad Nacional Autónoma de México, Mexico City, Mexico

    Luis J. Jara

  5. Department of Medicine ‘B’, Sheba Medical Center, Tel-Hashomer, Israel

    Yehuda Shoenfeld

  6. Sackler Faculty of Medicine, Incumbent of the Laura Schwarz-Kip Chair for Research of Autoimmune Diseases, Tel-Aviv University, Tel-Aviv, Israel

    Yehuda Shoenfeld

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  1. Honorio Torres-Aguilar
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Correspondence to Honorio Torres-Aguilar.

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Torres-Aguilar, H., Sánchez-Torres, C., Jara, L.J. et al. IL-10/TGF-β-Treated Dendritic Cells, Pulsed with Insulin, Specifically Reduce the Response to Insulin of CD4+ Effector/Memory T Cells from Type 1 Diabetic Individuals. J Clin Immunol 30, 659–668 (2010). https://doi.org/10.1007/s10875-010-9430-5

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